From Depression to Dementia: Genetic Variants in APOE and APOC1 Linked to Post-Depression Dementia in the UK Biobank

Introduction : Dementia, including Alzheimer’s disease (AD) and related disorders, affects more than 50 million individuals worldwide and is projected to increase substantially with population aging. Late life depression is a well established risk factor for subsequent dementia [1, 2]. Conversely, depressive symptoms are highly prevalent in patients with established dementia [3]. Several biological mechanisms have been proposed to explain this relationship. Dysregulation of the hypothalamic–pituitary–adrenal axis, neuroinflammation, vascular compromise, impaired neurotrophic signaling, and synaptic dysfunction have all been implicated in both depression and AD pathophysiology, yet the mechanisms underlying this transition and the extent to which risk can be stratified remain unclear. To investigate the genetic contribution to dementia risk following late life depression and to assess whether genetic liability may inform risk stratification.

Methods : We conducted a genome wide association study using data from 62,774 UK Biobank participants aged ≥ 65 years, including 2,851 individuals with post depression dementia, defined as dementia occurring after depression. Association testing was conducted using logistic regression under an additive genetic model, as implemented in the COMPASS platform, and Polygenic risk score(PRS) analyses were performed to evaluate the cumulative genetic contribution to dementia risk among individuals with prior depression. Manhattan plots, quantile-quantile plots, and regional association plots were generated within the analytic environment for dementia risk across diagnostic groups, adjusting for age, sex, smoking status, alcohol use, hypertension, and diabetes.

Results : Genome wide significant associations in post depression dementia were concentrated within the APOE region on chromosome 19, including rs769449 ( OR = 1.40, P = 1.79 × 10⁻¹⁷ ) and rs429358 (missense variant in APOE; OR = 1.38, P = 3.11 × 10⁻¹⁶ ), with additional signals in APOC1, NECTIN2 (rs6857, UTR variant in NECTIN2; OR = 1.34, P = 1.66 × 10⁻¹⁴ ), and TOMM40. In covariate-adjusted logistic regression models including age, sex, and the first ten genetic principal components, each one-standard-deviation increase in the PRS was associated with a 1.43-fold higher risk of dementia after depression (the PRS constructed using variants selected at P ≤ 0.5; odds ratio [OR] = 1.43, P = 1.87 × 10⁻¹¹). Similar results were observed when using a more inclusive threshold (P ≤ 1.0), yielding a comparable AUC (0.601) and effect size (OR per standard deviation = 1.44, P = 1.50 × 10⁻¹¹).

Conclusions: In this large population-based genome-wide association study, we observed that genetic signals associated with post-depression dementia (PDD) were primarily concentrated within the APOE region. Dementia following late life depression appears to reflect a continuum of vulnerability shaped by established Alzheimer’s disease genetic risk rather than a distinct subtype. These findings have clinical implications, supporting the potential utility of genetic risk stratification to identify high-risk individuals and inform targeted monitoring and early intervention strategies in older adults with depression.

References

1. Diniz BS, Butters MA, Albert SM, Dew MA, Reynolds CF. Late-life depression and risk of vascular dementia and Alzheimer’s disease: systematic review and meta-analysis. Br J Psychiatry 2013; 202: 329–335.
2. Shin JH, Park J, Jang Y, et al. Association of depressive symptoms with Alzheimer disease risk: systematic review and meta-analysis. JAMA Psychiatry 2023; 80: 1245–1254
3. World Health Organization. Global status report on the public health response to dementia. Geneva: World Health Organization; 2021.